TFEB-associated renal cell carcinoma: A case report and literature review

Rationale: TFEB-associated renal cell carcinoma is very rare and belongs to the microphthalmia — associated transcription family translocation renal cell carcinoma. Patient concerns: Hospitalized for fever, a 29-year-old male patient had a left kidney lesion without any additional discomfort. Diagnoses: Histopathological and immunohistochemical results were corresponding with TFEB renall cell carcinoma features. Interventions: Surgical resection of the tumor was performed. Outcomes: After 8 months of follow-up, no tumor recurrence was observed. Lessons: TFEB-associated renal cell carcinoma is rare. The diagnosis is explicit. However, the optimal treatment needs to be further explored.


Introduction
Various subtypes of renal cell carcinoma (RCC) have distinct histological characteristics, gene mutations, and clinical characteristics. In 2016, a new subtype, known as microphthalmia-associated transcription (MIT) family translocation renal cell carcinoma, was added to the WHO classification of renal cell carcinoma. [1] Renal cell carcinoma, which is composed of 4 transcription factors, microphthalmia -associated transcription factor (MITF), TFEC, TFEB, and TFE3, has been identified as an independent entity known as MITF translocation carcinoma. The latter 2 are associated with the development of renal cell carcinoma. include TFEB-related renal cell carcinoma and renal cell carcinoma linked to Xp11.2 translocation. [2] This study evaluated the pertinent literature and described a case of renal cell cancer linked to TFEB.

Case report
Hospitalized for fever, a 29-years-old male patient had a left kidney lesion without any discomfort. The physical examination revealed no abnormality. The size, shape, and Color Doppler ultrasonic color imaging results of kidneys were of normal size, and the capsule was smooth. A cystic solid nodule measuring approximately 4.2 * 4.5 cm was found in the upper of the left kidney. Some faint signs of blood flow were observed; however, the boundary was not clear. A computed tomography scan revealed an isodense, spherical mass measuring 5.9 * 4.9 * 6.0 cm in the upper pole of the left kidney (Fig. 1A), Contrast computed tomography scan showed uneven mild enhancement of tumor, no abnormal density, and enhancement of the right kidney (Fig.1B, C). A laparoscopic partial nephrectomy was performed on the left kidney. The postoperative specimens were grayish-white, grayish-brown, and soft. The internal tumor was grayish-yellow, grayish-red, soft, and cystic locally (Fig. 1D, E). The patients recovered well after operation. Adjuvant was not administered. Two months after the surgery, a low-density shadow was observed in the left kidney ( Fig. 2A). Five months after the surgery, the low-density shadow in the left kidney became smaller (Fig. 2B). The surgical video was reviewed, and the low-density shadow was considered the necrotic focus of the vascular ligation.

Discussion
MITF translocation renal cell carcinoma was classified as a separate subtype by the WHO in 2016. [1] MITF translocation renal cell carcinoma has been identified as an independent entity in renal cell carcinoma and consists of 4 transcription factors: MITF, TFEC, TFEB and TFE3. TFEB and TFE3 are associated with sporadic renal cell carcinoma. [2] MITF translocation renal cell carcinoma accounts for about 1/ 3 of ediatric renal tumors. Approximately 15% of patients with renal tumors under 40-years-old have MIT family translocation renal cell carcinoma, and the proportion of adult patients with renal tumors is up to 4%. [3,4] Including Xp11.2 translocation associated renal cell carcinoma and TFEB-associated renal cell carcinoma, [2,5] These partner genes fuse with TFE3 or TFEB genes and activate transcription to further activate downstream genes, resulting in tumorigenesis. [6,7] The TFEB-associated renal cell carcinoma fused alpha (MALAT1) gene and TFEB transcription factor gene result in up regulation of TFEB expression, thereby driving the abnormal expression of melanocyte markers, which is a sign of this unique tumor. [8] For example, Melan-A was expressed in this case. In addition, Zhan et al [9] showed that in cell lines stably transfected with α-TFEB, high expression of TFEB enhanced cell invasion, promoted cell proliferation, reduced cell apoptosis, and promoted tumorigenicity in nude mice. TFEB or TFE3 fusion with other partner genes   TFEB-associated renal cell carcinoma is very rare [10] , By 2017, only about 50 cases of TFEB-associated renal cell carcinoma were reported. [11] The main partner gene fused with TFEB is MALAT1 (also known as α gene). [12] Other fusion partner genes have recently been described as ACTB, NEAT1 [13] and melanin TFEB-associated renal cell carcinoma. [14] Fusion of TFEB translocation with other genes is a common feature of these tumors, and an increasing number of partner genes have been identified. Morphologically, the typical microscopic features of TFEB-associated renal cell carcinoma are biphasic distribution of large epithelioid cells and small cells, eosinophilic cytoplasm of large epithelioid cells, and absence of basement membrane spheres. [6,15,16] In terms of immunohistochemical markers, TFEB-associated renal cell carcinoma was not labeled as an epithelial immunohistochemical marker, but was labeled as melanocyte markers HMB45 and melan-A. [8] It was also reported that HMB45 and melan-A were negative, Sean R. Williamson et al speculated that a subgroup of TFEB-associated renal cell carcinoma lacked melanocyte markers. [17,18] In our reported cases, Melan-A was expressed without HMB45. Because the biphasic structure observed under a microscope, some diagnostic clues can be provided. [6,15,16] Immunohistochemical (IHC) of TFEB protein has diagnostic value in TFEB-associated renal cell carcinoma. However, due to the limitations of staining conditions and techniques, IHC results in false positive or false negative. Fluorescence in situ hybridization (FISH) is the gold standard for current diagnosis. [19][20][21][22] One of the differential diagnoses for TFEB-associated renal cell carcinoma is TFEBamplified renal cell carcinoma. These are all TFEB variants of renal cell carcinoma. FISH detection of TFEB protein is an effective identification method. In addition, IHC for MelanA is also an effective identification method, which is positive in 90 % and 60 % of TFEB-associated renal cell carcinomas and TFEBamplified renal cell carcinomas, respectively. [10] Another differential point is epithelioid angiomyolipoma, both of which show significant IHC overlap, consistently label melanocyte markers and cathepsin K, usually label CD117 and vimentin. PAX8 is a specific marker for distinguishing TFEB-associated renal cell carcinoma from epithelioid angiomyolipoma. But unfortunately has low sensitivity, as not all TFEB-associated renal cell carcinomas express PAX8.In which case FISH may be an effective method for this distinction. [23] In summary, for TFEB-associated renal cell carcinoma, in the diagnosis and differential diagnosis of translocation renal cell carcinoma and other types of renal cell carcinoma, even between MIT family translocation renal cell carcinoma, morphology, and IHC are good identification methods, and FISH is sometimes necessary.
Surgery is the preferred treatment; however, there are no clear guideline for its treatment. [24] In TFEB-associated renal cell carcinoma, overexpression of mTORC1 induced by TFEB is a key step in kidney, bladder formation and tumorigenesis. [25] Zhang et al [26] found that TFEB binds to PD-L1 promoter in RCC and inhibits mTOR, leading to nuclear translocation of TFEB and enhanced expression of PD-L1. In an RCC xenograft mouse model, inhibition of mTOR and blocking of PD-L1 enhanced CD8 + cell lysis and tumor suppression. This suggest that immunotherapy and targeted therapy have therapeutic effects in TFEB-associated renal cell carcinoma. It has been shown to be related to biphasic morphology. [23,27] Comprehensive analysis  provides a favorable basis for PD-L1 as an immunotherapy or targeted therapy for TFEB-associated renal cell carcinoma, but further studies are necessary. In terms of prognosis, some studies have showed that most TFEB-associated renal cell carcinoma exhibit inert behavior, and approximately 17% of the cases exhibit invasive behavior. [13] Wyvekens et al [10,28] also pointed out that TFEB-associated renal cell carcinoma seems to have a better prognosis. Seven patients with TFEB-associated renal cell carcinoma were followed-up by Rao et al During an average follow-up period of 31 months, no tumor recurrence, progression or metastasis occurred in any patient. [29] To date, there are no factor to predict tumor invasiveness. [30] Progression of TFEBassociated renal cell carcinoma is slow and inert. However, existing studies have limitations such as fewer cases and a short follow-up time. Additional cases and longer follow-up periods are required.
In summary, we reported a case of MIT family translocation renal cell carcinoma and review the relevant literature. TFEB-associated renal cell carcinoma translocation-fused alpha (MALAT1) and TFEB transcription factor genes. The morphology of these patients was related to the TFEB and showed a typical biphasic structure. TFEB-associated renal cell carcinoma was not marked as an epithelial immunohistochemical marker but was marked as melanocyte markers HMB45 and melan-A. IHC is an effective screening method for the TFEB protein, and FISH is the gold standard for diagnosis. Surgery is the primary treatment option. Targeted therapy and immunotherapy may be effective treatments for these conditions. Many studies have reported that TFEB-associated renal cell carcinoma has inert behavior.

Author contributions
Investigation: Lin Li.